Advances in prevention, treatment and nursing of anastomotic leakage following laparoscopic colorectal cancer surgery
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摘要:
结直肠癌是常见的消化系统恶性肿瘤之一，腹腔镜手术作为微创手术方式，具有创伤小、恢复快、住院时间短等优点，逐渐成为消化道系统疾病治疗的主流选择。但是术后吻合口瘘仍然是该手术严重并发症之一，对患者的康复和预后造成影响。本综述旨在汇总和分析近年来腹腔镜结直肠癌术后吻合口瘘的相关研究，探讨其发生机制、危险因素、预防策略、治疗及护理措施，为临床实践提供科学依据和指导。
Abstract:Colorectal cancer is one of the common malignancies of the digestive system. Laparoscopic surgery, as a minimally invasive procedure, has advantages such as minimal trauma, rapid recovery, and shortened hospital stay, gradually becoming a main choice for treatment of digestive system diseases. However, anastomotic leakage remains one of the serious complications following this surgery, impacting patients'recovery and prognosis. This review aimed to summarize and analyze recent research on anastomotic leakage after laparoscopic colorectal cancer surgery, exploring its pathogenesis, risk factors, preventive strategies, treatment and nursing measures, in order to provide a scientific basis and guidance for clinical practice.
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高迁移率族蛋白B1(HMGB1)是一种广泛分布于肺、肝等脏器的晚期促炎因子，参与脓毒症的发生及病情进展过程[1]。研究[2]发现, HMGB1异常升高与脓毒症患者病情严重程度有关，且可作为判断患者预后的血清指标。可溶性髓样细胞触发受体样转录因子-1(sTLT-1)是一种由血小板表面髓细胞激发受体样转录因子-1(TLT-1)产生的蛋白质，当机体发生炎症时，其水平急性升高[3]。本研究通过检测脓毒症患者血清HMGB1、sTLT-1水平，探讨其对脓毒症急性肺损伤(ALI)发生的潜在预测价值。
1. 资料与方法
1.1 一般资料
选取2019年1月—2021年1月收治的脓毒症患者160例为研究对象。纳入标准: ①患者均符合脓毒症的相关诊断标准[4]; ②临床资料完整者; ③患者及家属均自愿签署知情同意书。排除标准: ①住院时间 < 48 h; ②患者伴急性肺炎、慢性阻塞性肺疾病等呼吸系统疾病; ③既往有肺动脉高压病史者; ④合并心、肝、肾等重要脏器功能不全者; ⑤合并肿瘤、血液系统疾病或免疫系统疾病者。根据住院期间是否出现ALI[6], 将160例脓毒症患者分为ALI组(n=47)和非ALI组(n=113)。本研究经川北医学院附属医院伦理委员会批准通过。
1.2 方法
收集患者一般资料信息，包括年龄、体质量指数(BMI)、性别、高血压史、糖尿病史、冠心病史、吸烟史、气管插管、心率、氧合指数[pa(O2)/FiO2]及序贯器官衰竭(SOFA)评分情况。实验室指标取患者入院后的第1次检查结果，包括血小板计数、白细胞计数、血肌酐、C反应蛋白(CRP)及N-端脑利钠肽前体(NT-proBNP)。抽取患者入院24 h内空腹静脉血5 mL, 离心后(3 500转/min离心10 min)提取上清液。采用酶联免疫吸附法检测血清HMGB1、sTLT-1水平，参照试剂盒(由上海联迈生物科技有限公司提供)说明书进行检测。
1.3 统计学方法
采用SPSS 25.0统计学软件进行数据录入和分析。计数资料以[n(%)]表示，非ALI组和ALI组间比较行χ2检验; 计量资料以均数±标准差表示，非ALI组和ALI组间比较采用t检验。Pearson法分析脓毒症ALI患者血清HMGB1、sTLT-1水平与相关指标的关系; 多因素Logistic回归分析影响脓毒症ALI的危险因素; ROC曲线分析血清HMGB1、sTLT-1水平对脓毒症患者发生ALI的预测价值，曲线下面积比较行Z检验。P < 0.05为差异有统计学意义。
2. 结果
2.1 非ALI组和ALI组患者一般资料比较
非ALI组和ALI组患者年龄、BMI、心率、血小板计数、白细胞计数、血肌酐及男性、高血压史、糖尿病史、冠心病史、吸烟史、气管插管患者占比比较，差异均无统计学意义(P>0.05); ALI组患者pa(O2)/FiO2低于非ALI组, SOFA评分、CRP及NT-proBNP高于非ALI组，差异有统计学意义(P < 0.05), 见表 1。
表 1 非ALI组和ALI组患者一般资料比较(x±s)[n(%)]项目 非ALI组(n=113) ALI组(n=47) 年龄/岁 61.07±7.94 61.43±9.82 体质量指数/(kg/m2) 23.42±2.17 23.16±2.04 男性 60(53.10) 27(57.45) 高血压史 66(58.41) 30(63.83) 糖尿病史 20(17.70) 11(23.40) 冠心病史 39(34.51) 18(38.30) 吸烟史 26(23.01) 15(31.91) 气管插管 9(7.96) 8(17.02) 心率/(次/min) 103.51±12.94 107.14±11.88 氧合指数/mmHg 346.92±40.83 259.30±38.67* 序贯器官衰竭评分/分 3.74±0.95 5.20±1.33* 血小板计数/(×109/L) 108.39±25.85 102.44±26.93 白细胞计数/(×109/L) 12.27±3.10 12.98±3.26 血肌酐/(μmol/L) 135.61±34.00 140.15±38.21 C反应蛋白/(mg/L) 82.91±21.72 97.54±25.38* NT-proBNP/(ng/L) 2 036.09±668.34 3 195.47±1 006.52* NT-proBNP: N-端脑利钠肽前体。与非ALI组比较, *P < 0.05。 2.2 非ALI组和ALI组患者血清HMGB1、sTLT-1水平比较
ALI组患者血清HMGB1、sTLT-1水平均高于非ALI组，差异有统计学意义(P < 0.05)。见表 2。
表 2 非ALI组和ALI组患者血清HMGB1、sTLT-1水平比较(x±s)pg/mL 组别 n HMGB1 sTLT-1 非ALI组 113 56.60±15.77 531.24±138.21 ALI组 47 72.19±20.08* 601.85±162.49* HMGB1: 高迁移率族蛋白B1;
sTLT-1: 可溶性髓样细胞触发受体样转录因子-1。
与非ALI组比较, *P < 0.05。2.3 脓毒症ALI患者血清HMGB1、sTLT-1水平与相关指标的关系
脓毒症ALI患者血清HMGB1、sTLT-1水平与pa(O2)/FiO2呈负相关，与SOFA评分、CRP、NT-proBNP呈正相关(P < 0.05), 见表 3。
表 3 脓毒症ALI患者血清HMGB1、sTLT-1水平与相关指标的关系指标 HMGB1 sTLT-1 r P r P 氧合指数 -0.533 < 0.001 -0.409 < 0.001 序贯器官衰竭评分 0.401 < 0.001 0.536 < 0.001 C反应蛋白 0.367 0.007 0.512 < 0.001 N-端脑利钠肽前体 0.548 < 0.001 0.380 0.002 HMGB1: 高迁移率族蛋白B1;
sTLT-1: 可溶性髓样细胞触发受体样转录因子-1。2.4 多因素Logistic回归分析影响脓毒症ALI的危险因素
以脓毒症患者是否发生ALI为因变量(1=是, 0=否)，将pa(O2)/FiO2、SOFA评分、CRP、NT-proBNP、HMGB1、sTLT-1为自变量(均为实测值)进行多因素Logistic回归分析，结果发现pa(O2)/FiO2、SOFA评分及血清HMGB1、sTLT-1水平均是影响脓毒症ALI发生的危险因素(P < 0.05), 见表 4。
表 4 多因素Logistic回归分析影响脓毒症ALI的危险因素变量 β SE Wald P OR 95%CI pa(O2)/FiO2 0.454 0.169 7.205 0.007 1.574 1.130~2.192 SOFA评分 0.553 0.202 7.487 0.006 1.738 1.170~2.582 CRP 0.087 0.126 0.478 0.489 1.091 0.852~1.397 NT-proBNP 0.152 0.153 0.985 0.321 1.164 0.862~1.571 HMGB1 0.766 0.228 11.285 0.001 2.151 1.376~3.363 sTLT-1 0.604 0.197 9.393 0.002 1.829 1.243~2.691 pa(O2)/FiO2: 氧合指数; SOFA: 序贯器官衰竭; CRP: C反应蛋白; NT-proBNP: N-端脑利钠肽前体;
HMGB1: 高迁移率族蛋白B1; sTLT-1: 可溶性髓样细胞触发受体样转录因子-1。2.5 血清HMGB1、sTLT-1水平对脓毒症患者发生ALI的预测价值
血清HMGB1、sTLT-1水平联合预测脓毒症患者发生ALI的曲线下面积为0.910, 高于血清HMGB1水平(Z=2.119, P=0.034)及血清sTLT-1水平(Z=2.846, P=0.004)单独预测，其预测敏感度为78.70%, 特异度为89.40%, 见表 5、图 1。
表 5 血清HMGB1、sTLT-1水平对脓毒症患者发生ALI的预测价值指标 曲线下面积 最佳临界值/(pg/mL) 敏感度/% 特异度/% P 95%CI HMGB1 0.823 64.74 80.90 72.60 < 0.001 0.756~0.890 sTLT-1 0.786 575.51 87.20 62.80 < 0.001 0.713~0.859 两者联合 0.910 — 78.70 89.40 < 0.001 0.865~0.955 3. 讨论
HMGB1是一种保守的非组蛋白核蛋白，参与DNA复制、重组、转录及修复过程[6]。HMGB1作为与脓毒症、恶性肿瘤、免疫性疾病相关的晚期炎症因子，在炎症反应中发挥重要作用[7]。王立鹤等[8]研究报道, HMGB1在脓毒症患者血清中水平较高，其水平异常升高与患者不良预后有关。崔文娟等[9]研究发现，外周血HMGB1水平升高与脓毒症患者急性肾损伤发生有一定关联。本研究结果显示, ALI组患者血清HMGB1水平较非ALI组高，且与pa(O2)/FiO2呈负相关，与SOFA评分、CRP、NT-proBNP呈正相关，与王立鹤等[8]、崔文娟等[9]研究相似，提示血清HMGB1水平升高参与了脓毒症患者ALI的发生。研究[10]报道称, HMGB1可能通过激活巨噬细胞中的黑色素瘤2炎性小体，并通过Toll样受体2/4和晚期糖基化终产物受体/核因子κB信号通路诱导M1巨噬细胞极化来参与ALI的发病过程。另有研究[11]发现，经脂多糖处理，促炎因子白细胞介素-1、肿瘤坏死因子-α和HMGB1表达导致微血管形成，促进内皮细胞增殖、迁移，核因子κB核转位导致炎症因子释放，进而诱导ALI、细胞凋亡及自噬; 炎症因子进一步促进HMGB1释放，形成正反馈回路，放大炎症级联反应，加重组织损伤，推测HMGB1可能与相关炎性因子相互作用调控脓毒症患者病情发展。
TLT-1是一种1型免疫球蛋白结构域受体，储存在血小板α颗粒中，当血小板被激活时，一部分TLT-1会转移到细胞表面，以sTLT-1形式释放进入外循环。近年来, sTLT-1在血管疾病中的作用越来越受到重视。FU R等[12]研究发现, sTLT-1在急性冠状动脉综合征患者血清中水平升高，随着治疗的进展, sTLT-1水平在各个时点均有明显变化，从而降低血清中sTLT-1水平，提高胆红素水平，有利于改善患者预后。另有研究[13]表明, sTLT-1可调节血小板、白细胞和内皮细胞增殖、迁移，内皮细胞通过促进肌动蛋白聚合附着在血管内皮细胞上，从而诱导动脉粥样硬化的发生，促进冠心病的发展。在脂多糖诱导的ALI小鼠模型中，注射sTLT-1可使血小板-中性粒细胞结合物比例增加47%, 证实了sTLT-1参与了ALI炎症反应[14]。本研究结果显示, ALI组患者血清sTLT-1水平较非ALI组高，且与pa(O2)/FiO2呈负相关，与SOFA评分、CRP、NT-proBNP呈正相关，与MORALES-ORTÍZ J等[15]研究结果类似，提示sTLT-1可能参与脓毒症患者病情进展过程，具体作用方式和机制有待进一步研究。多因素Logistic回归分析结果显示，血清HMGB1、sTLT-1是脓毒症ALI发生的危险因素，且两者均对ALI有一定的预测价值，联合预测效能最高，表明检测血清HMGB1、sTLT-1水平对脓毒症ALI患者病情发展、治疗干预具有一定临床指导意义。
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